Renal tubule injury (also referred to herein as, “tubular nephrosis”) is a common drug-induced toxicity that includes degenerative lesions of the renal tubules, such as acute tubular dilation, vacuolation and necrosis. Necrotic lesions of the tubules can arise as a consequence of septic, toxic or ischemic insult, and is a frequent cause of renal failure among hospitalized patients. Recognition is hampered by the lack of accurate markers and the shortcomings and over-reliance of serum markers of impaired glomerular filtration rate (i.e., serum creatinine and blood urea nitrogen) (see e.g., Schrier et al., “Acute renal failure: definitions, diagnosis, pathogenesis, and therapy,” J Clin Invest, 114(1):5-14 (2004)). Drugs associated with the development of tubular nephrosis include aminoglycoside antibiotics, antifungals, antineoplastics, immunosuppresants and radiocontrast dyes, among others.
Similarly to the human clinical setting, long-term treatment of rats during preclinical drug development with relatively low doses of aminoglycoside antibiotics, heavy metal toxicants or antineoplastic drugs, for example, leads to the development of degenerative lesions of the renal tubules. However, histopathological or clinical indications of kidney injury are not readily apparent in the early course of treatment, thus necessitating expensive and lengthy studies.
The development of methods to predict the future onset of renal tubule injury (RTI) and gain a greater understanding of the underlying mechanism, would facilitate the development more reliable clinical diagnostics and safer therapeutic drugs. In addition, improved preclinical markers for RTI would dramatically reduce the time, cost, and amount of compound required in order to prioritize and select lead candidates for progression through drug development.